Project Summary/Abstract Stress is implicated in cognitive dysfunctions that characterize many psychiatric diseases, including depression, substance abuse and post-traumatic stress disorder. One mechanism by which stressors impact on cognition is through their engagement of monoamine systems that regulate activity of the prefrontal cortex (PFC) that governs executive functions. The locus-coeruleus (LC)-norepinephrine (NE) system, is a major stress response system that initiates arousal and modulates cognitive flexibility in response to stressors through its regulation of the PFC. Stress-induced engagement of the LC-NE system is mediated by CRF neurotransmission. It has been hypothesized that stress-induced impairments in executive function arise from excessive LC-NE drive to the medial PFC (mPFC) and resulting inhibition of mPFC function. This important hypothesis has never been directly tested. Although the activating effects of stressors and CRF on activity of single LC neurons have been well described, a major gap exists in our understanding of how these single cellular events translate to changes in cortical activity that then govern executive functions such as cognitive flexibility. To address this question, this research will quantify network activity in response to CRF or stress in a circuit linking the LC with the mPFC and the orbitofrontal cortex (OFC), PFC subregions that have been implicated in different cognitive processes. Network activity is the synchronization of neural oscillations that supports communication between brain regions and is recorded by local field potentials (LFPs). The following Aims will quantify LC-PFC network dynamics, including their strength, connectivity and directionality by recording LFPs in these regions in response to stress and CRF and determining how these effects translate to changes in cognitive flexibility. Because stress-related psychiatric diseases are more prevalent in females and female LC neurons are more sensitive to CRF compared to males, this research will also reveal the role of sex as a determinant of stress effects. Aim 1 will identify the effects of activating CRF1 or Gs-protein-related signaling in LC neurons on network activity within the LC-PFC circuit. These effects will be examined at rest and during performance of tasks that test cognitive flexibility. Aim 2 will identify the effects of acute and repeated social stress (resident-intruder stress) on LC-PFC network activity, and will dissect the role of CRF in the LC in these effects. Aim 3 will determine whether repeated social stress has enduring effects on LC-PFC network activity that translate to changes in cognitive flexibility. Together these studies take a network approach to elucidate how cellular effects of stress on LC neurons are amplified to cortical circuits to affect cognitive flexibility, an important attribute of executive function that is impaired in multiple stress-related psychiatric disorders.